Human Genetics

, Volume 114, Issue 1, pp 87–98 | Cite as

Evidence for substantial effect modification by gender in a large-scale genetic association study of the metabolic syndrome among coronary heart disease patients

  • Jeanette J. McCarthy
  • Joanne Meyer
  • David J. Moliterno
  • L. Kristin Newby
  • William J. Rogers
  • Eric J. Topol
Original Investigation


Major genetic determinants of the metabolic syndrome — a clustering of abdominal obesity, high triglycerides, low HDL cholesterol, high blood pressure and high fasting glucose — remain elusive. We surveyed 207 single-nucleotide polymorphisms in 110 candidate genes among coronary artery disease patients, a population enriched for metabolic abnormalities. The number of abnormalities (0–5) was determined in the 214 male and 91 female patients, and the association with each polymorphism evaluated by means of ordinal regression analysis. Polymorphisms in eight genes, including LDLR, GBE1, IL1R1, TGFB1, IL6, COL5A2, SELE and LIPC, were associated with metabolic syndrome in the whole population (P values ranged from 0.047 to 0.008). Variants in seven additional genes showed significant gene by gender interaction. Among these, separate analyses in men and women revealed a strong association with a silent polymorphism in the low-density lipoprotein receptor-related protein gene, LRPAP1, among females (P=0.0003), but not males (P=0.292). Other genes associated only in females included THBS1, ACAT2, ITGB3, F2 and SELP (P values ranging from 0.032 to 0.002). Only one gene (PRCP) was significantly associated in men alone (P=0.039). Our results propose several new candidate genes for the metabolic syndrome and suggest that the genetic basis of this syndrome may be strongly modified by gender.


Metabolic Syndrome Abdominal Obesity Metabolic Abnormality Coronary Artery Disease Patient Metabolic Trait 


  1. Allayee H, de Bruin TW, Michelle Dominguez K, Cheng LS, Ipp E, Cantor RM, Krass KL, Keulen ET, Aouizerat BE, Lusis AJ, Rotter JI (2001) Genome scan for blood pressure in Dutch dyslipidemic families reveals linkage to a locus on chromosome 4p. Hypertension 38:773–778PubMedGoogle Scholar
  2. Broeckel U, Hengstenberg C, Mayer B, Holmer S, Martin LJ, Comuzzie AG, Blangero J, Nurnberg P, Reis A, Riegger GA, Jacob HJ, Schunkert H (2002) A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nat Genet 30:210–214CrossRefPubMedGoogle Scholar
  3. Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES (1999) Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 22:231–238PubMedGoogle Scholar
  4. Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927PubMedGoogle Scholar
  5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 285:2486–2497PubMedGoogle Scholar
  6. Ford ES, Giles WH, Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287:356–359PubMedGoogle Scholar
  7. Francke S, Manraj M, Lacquemant C, Lecoeur C, Lepretre F, Passa P, Hebe A, Corset L, Yan SL, Lahmidi S, Jankee S, Gunness TK, Ramjuttun US, Balgobin V, Dina C, Froguel P (2001) A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27. Hum Mol Genet 10:2751–2765CrossRefPubMedGoogle Scholar
  8. Gonzalez P, Alvarez R, Reguero JR, Batalla A, Alvarez V, Cortina A, Cubero GI, Garcia-Castro M, Coto E (2002) Variation in the lipoprotein receptor-related protein, alpha2-macroglobulin and lipoprotein receptor-associated protein genes in relation to plasma lipid levels and risk of early myocardial infarction. Coron Artery Dis 13:251–254CrossRefPubMedGoogle Scholar
  9. Groop L (2000) Genetics of the metabolic syndrome. Br J Nutr 83 Suppl 1:S39–48Google Scholar
  10. Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP (1992) Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes 41:715–722PubMedGoogle Scholar
  11. Herz J, Strickland DK (2001) LRP: a multifunctional scavenger and signaling receptor. J Clin Invest 108:779–784PubMedGoogle Scholar
  12. Hirschhorn JN, Sklar P, Lindblad-Toh K, Lim YM, Ruiz-Gutierrez M, Bolk S, Langhorst B, Schaffner S, Winchester E, Lander ES (2000) SBE-TAGS: an array-based method for efficient single-nucleotide polymorphism genotyping. Proc Natl Acad Sci USA 97:12164–12169CrossRefPubMedGoogle Scholar
  13. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L (2001) Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24: 683–689PubMedGoogle Scholar
  14. Kissebah AH, Sonnenberg GE, Myklebust J, Goldstein M, Broman K, James RG, Marks JA, Krakower GR, Jacob HJ, Weber J, Martin L, Blangero J, Comuzzie AG (2000) Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA 97:14478–14483CrossRefPubMedGoogle Scholar
  15. Kloting I, Kovacs P, van den Brandt J (2001) Sex-specific and sex-independent quantitative trait loci for facets of the metabolic syndrome in WOKW rats. Biochem Biophys Res Commun 284:150–156CrossRefPubMedGoogle Scholar
  16. Kuhar MB (2002) Update on managing hypercholesterolemia. The new NCEP guidelines. AAOHN J 50:360–364PubMedGoogle Scholar
  17. Lewontin R (1964) The interaction of selection and linkage. I. General considerations; heterotic models. Genetics 49:49–67Google Scholar
  18. Livak KJ (2003) SNP genotyping by the 5′-nuclease reaction. Methods Mol Biol 212:129–147PubMedGoogle Scholar
  19. McCarthy J, Lehner T, Reeves C, Moliterno D, Newby L, Rogers W, Topol E (2003) Association of genetic variants in the HDL receptor, SR-BI, with abnormal lipids in women with coronary artery disease. J Med Genet (in press)Google Scholar
  20. Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB (2003) The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 163:427–36CrossRefPubMedGoogle Scholar
  21. Poulsen P, Vaag A, Kyvik K, Beck-Nielsen H (2001) Genetic versus environmental aetiology of the metabolic syndrome among male and female twins. Diabetologia 44:537–543CrossRefPubMedGoogle Scholar
  22. Sanchez L, Alvarez V, Gonzalez P, Gonzalez I, Alvarez R, Coto E (2001) Variation in the LRP-associated protein gene (LRPAP1) is associated with late-onset Alzheimer disease. Am J Med Genet 105:76–78CrossRefPubMedGoogle Scholar
  23. Topol EJ, McCarthy J, Gabriel S, Moliterno DJ, Rogers WJ, Newby LK, Freedman M, Metivier J, Cannata R, O’Donnell CJ, Kottke-Marchant K, Murugesan G, Plow EF, Stenina O, Daley GQ (2001) Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation 104:2641–2644PubMedGoogle Scholar
  24. Willnow TE, Armstrong SA, Hammer RE, Herz J (1995) Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo. Proc Natl Acad Sci USA 92:4537–4541PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Jeanette J. McCarthy
    • 1
  • Joanne Meyer
    • 2
  • David J. Moliterno
    • 3
  • L. Kristin Newby
    • 4
  • William J. Rogers
    • 5
  • Eric J. Topol
    • 3
  1. 1.School of Public HealthSan Diego State UniversitySan DiegoUSA
  2. 2.Millennium PharmaceuticalsCambridgeUSA
  3. 3.Cleveland Clinic FoundationClevelandUSA
  4. 4.Duke University Medical CenterDurhamUSA
  5. 5.University of Alabama Medical CenterBirminghamUSA

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